This invention relates to novel bicyclic derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor. Thus, the compounds of the present invention, which are selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. In addition to receptor tyrosine kianses, the compounds of the present invention can also display inhibitory activity against a variety of other non-receptor tyrosine kinases (eg: Ick, src, abl) or serine/threonine kinases (e.g.: cyclin dependent kinases).
Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently, five European patent publications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published Nov. 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose.
The present invention relates to compounds of the formula 1
and to pharmaceutically acceptable salts and solvates thereof, wherein:
X is N or CH;
A represents a fused 5, 6 or 7-membered ring optionally containing 1 to 4 heteroatoms which may be the same or different and which are selected from xe2x80x94N(R1)xe2x80x94, O, and S(O)j, wherein j is an integer from 0 to 2, the fused ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused wherein the R1 group attached to the nitrogen is absent if a double bond includes the foregoing optional nitrogen moiety xe2x80x94N(R1)xe2x80x94, with the proviso that the fused ring does not form part of a purine and that the fused ring does not contain two adjacent O or S(O)1 atoms, and wherein the carbon atoms of the A moiety are optionally substituted with 1 to 3 R5 groups;
each R1 and R2 is independently H or C1-C6 alkyl;
R3 is xe2x80x94(CR1R2)mxe2x80x94R8 wherein m is 0 or 1;
or R1 and R3 are taken together to form a group of the formula 
wherein said group is optionally substituted with 1 to 3 R5 groups;
R4 is xe2x80x94(CR1R2)mxe2x80x94Cxe2x89xa1Cxe2x80x94(CR1R2)tR9, xe2x80x94(CR1R2)mxe2x80x94Cxe2x95x90Cxe2x80x94(CR1R2)txe2x80x94R9, xe2x80x94Cxe2x95x90NOR12, or xe2x80x94X1xe2x80x94R12 wherein m is an integer from 0 to 3, t is an integer from 0 to 5, and X1 is a divalent group derived from azetidine, oxetane or a C3-C4 carbocyclic group;
or R4 is xe2x80x94(CR1R2)mxe2x80x94Cxe2x89xa1Cxe2x80x94(CR1R2)kR13 or xe2x80x94(CR1R2)mxe2x80x94Cxe2x95x90xe2x80x94(CR1R2)kR13 wherein k is an integer from 1 to 3 and m is an integer from 0 to 3;
or R4 is xe2x80x94(CR1R2)tR9, wherein t is an integer from 0 to 5 and the attachment point to R9 is through a carbon atom of the R9 group;
each R5 is independently selected from halo, hydroxy, xe2x80x94NR1R2, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, trifluoromethoxy, xe2x80x94C(O)R6, xe2x80x94CO2R6, xe2x80x94NR6C(O)R1, xe2x80x94C(O )NR6R7, xe2x80x94SO2NR6R7, xe2x80x94NR6C(O)NR7R1, and xe2x80x94NR6C(O)OR7;
each R6 and R7is independently selected from H, C1-C6 alkyl, xe2x80x94(CR1R2)t(C6-C10 aryl), and xe2x80x94(CR1R2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (xe2x95x90O) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R6 and R7 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, xe2x80x94NR1R2, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, and C1-C6 alkoxy;
R8 is independently selected from xe2x80x94(CR1R2)t(C6-C10 aryl) and xe2x80x94(CR1R2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (xe2x95x90O) moiety, and each of the foregoing R8 groups is optionally substituted with 1 to 5 R10 groups;
R9 is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, wherein said ring contains from 3 to 12 carbon atoms in which from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S(O)j wherein j is an integer from 0 to 2, and xe2x80x94NR12xe2x80x94, provided that two O atoms, two S(O)j moieties, an O atom and a S(O)j moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other within said ring, and wherein the carbon atoms of said ring are optionally substituted with 1 to 2 R11 groups;
each R10 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C1-C6 alkoxy, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, xe2x80x94C(O)R6, xe2x80x94C(O)OR6, xe2x80x94OC(O)R6, xe2x80x94NR6C(O)R7, xe2x80x94NR6C(O)NR1R7, xe2x80x94NR6C(O)OR7, xe2x80x94C(O)NR6R7, xe2x80x94NR6R7, xe2x80x94NR6OR7, xe2x80x94SO2NR6R7, xe2x80x94S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, xe2x80x94(CR1R2)t(C6-C10 aryl), xe2x80x94(CR1R2)t(4-10 membered heterocyclic), xe2x80x94(CR1R2)qC(O)(CR1R2)t(C6-C10 aryl), xe2x80x94(CR1R2)qC(O)(CR1R2)t(4-10 membered heterocyclic), xe2x80x94(CR1R2)tO(CR1R2)q(C6-C10 aryl), xe2x80x94(CR1R2)q(CR1R2)q(4-10 membered heterocyclic), xe2x80x94(CR1R2)qS(O)j(CR1R2)t(C6-C10 aryl), and xe2x80x94(CR1R2)qS(O)j(CR1R2)t(4-10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R10 groups are optionally substituted with an oxo (xe2x95x90O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R10 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR6, xe2x80x94C(O)R6, xe2x80x94C(O)OR6, xe2x80x94OC(O)R6, xe2x80x94NR6C(O)R7, xe2x80x94C(O)NR6R7, xe2x80x94NR6R7, xe2x80x94NR6OR7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CR1R2)t(C6-C10 aryl), and xe2x80x94(CR1R2)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
each R11 is independently selected from xe2x80x94R12, xe2x80x94OR1, xe2x80x94NR1R2, xe2x80x94NR6C(O)R7, xe2x80x94NR6C(O)NR7R1, xe2x80x94NR6C(O)OR7, and xe2x80x94NR6SO2NR7R1, or R11 replaces two hydrogen atoms on a carbon to form an oxo (Cxe2x95x90O) group;
R12 is R6, xe2x80x94C(O)R6 or xe2x80x94SO2R6, xe2x80x94C(O)NR6R7, xe2x80x94SO2NR6R7, or xe2x80x94CO2R6;
R13 is xe2x80x94NR1R12 or xe2x80x94OR12;
and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halo, C1-C4 alkyl, C1-C4 alkoxy and xe2x80x94NR1R2.
In a specific embodiment of the present invention, the A moiety of the compounds of formula 1 is selected from 
wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5 groups as substituents.
Other specific embodiments of the compounds of formula 1 include those wherein A is selected from 
wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5 groups as substituents.
Other specific embodiments of the compounds of formula 1 include those wherein A is selected from 
wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5 groups as substituents.
Other specific embodiments of the compounds of formula 1 include those wherein A is selected from 
wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5 groups as substituents.
Other specific embodiments of the compounds of formula 1 include those wherein A is 
wherein the above A moieties bear an R4 group as a substituent and optionally bear 1 to 3 R5 groups as substituents.
Other specific embodiments of the compounds of formula 1 include those wherein R4 is xe2x80x94(CR1R2)mxe2x80x94Cxe2x89xa1Cxe2x80x94(CR1R2)tR9wherein m is an integer from 0-3 and t is an integer from 0-5.
Other specific embodiments of the compounds of formula 1 include those wherein R4 is xe2x80x94(CR1R2)mxe2x80x94Cxe2x95x90Cxe2x80x94(CR1R2)txe2x80x94R9and m is an integer from 0 to 3 and t is an integer from 0-5.
Other specific embodiments of the compounds of formula 1 include those wherein R4 xe2x80x94(CR1R2)mxe2x80x94Cxe2x89xa1Cxe2x80x94(CR1R2)kR13 or xe2x80x94(CR1R2)mxe2x80x94Cxe2x95x90Cxe2x80x94(CR1R2)kR13 wherein m is an integer from 0-3 and k is an integer from 1 to 3
Other specific embodiments of the compounds of formula 1 include those wherein R4 is is xe2x80x94Cxe2x95x90NOR12, or xe2x80x94X1-R12 wherein X1 is a divalent group derived from azetidine, oxetane or a C3-C4 carbocyclic group; or R4 is xe2x80x94(CR1R2)tR9, wherein the attachment point to R9 is through a carbon atom of R9.
Other specific embodiments of the compounds of formula 1 include those wherein R8 is selected from xe2x80x94(CR1R2)t(phenyl), xe2x80x94(CR1R2)t(pyridyl), xe2x80x94(CR1R2)t(pyrimidinyl), xe2x80x94(CR1R2)t(indolyl), xe2x80x94(CR1R2)t(indazolyl) and xe2x80x94(CR1R2)t(benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R8 groups is optionally substituted with 1 to 5 R10 groups.
Other specific embodiments of the compounds of formula 1 include those wherein R9 is a 4 to 10 membered heterocyclic group having 1 to 3 hetero moieties as indicated in formula 1 above and wherein said R9 is optionally substituted with 1 to 2 R11 groups.
Preferred compounds include those selected from the group consisting of:
Acetic acid 3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allyl ester;
(1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-quinazolin-4-yl}-amine;
(1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-pyrrolidin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine;
4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;
(1-Benzenesulfonyl-1H-indol-5-yl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;
[6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(1-benzenesulfonyl-1H-indol-5-yl)-amine;
1-Methyl-4-{4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylethynyl}-piperidin-4-ol;
1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;
4-{4-[4-(1-Phenyl-ethoxy)-phenylamino]-quinazolin-6-ylethynyl}-tetrahydro-pyran-4-ol;
1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4,4-dimethyl-pent-1-yn-3-ol;
4,4-Dimethyl-1-{4-[4-(1-phenyl-ethoxy)-phenylamino]-quinazolin-6-yl}-pent-1-yn-3-ol;
3-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;
1-Methyl-3-[4-(4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]- piperidin-3-ol;
3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-ol;
5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazolidin-2-one;
4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol;
4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;
3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
In accordance with the present invention, the most preferred compounds include those selected from the group consisting of:
(+)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(R)-ylethynyl-quinazolin-4-yl)-amine;
(xe2x88x92)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(S)-ylethynyl-quinazolin-4-yl)-amine;
3-(S)-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide;
3-(S)-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide;
(3-Methyl-4-phenoxy-phenyl)-(6-pyrrolidin-3-ylethynyl-quinazolin-4-yl)-amine;
3-[4-(5-Methyl-6-phenoxy-pyridin-3-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
(xe2x88x92)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
(+)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol;
{6-[l -(2-Methoxy-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;
[4-(2-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;
[4-(3-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;
(6-Azetidin-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine;
3-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;
3-{4-[4-(3-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;
4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;
(3-Chloro-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;
3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1]octan-3-ol;
(3-Chloro-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;
3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol;
3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-7-ylethynyl]-piperidin-3-ol;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
Other preferred compounds include those selected from the group consisting of:
N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;
N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;
(3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;
4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid methylamide;
{6-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;
1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperidin-4-ol;
N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;
N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-methyl-prop-2-ynyl}-acetamide;
N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;
4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-ol;
3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(3-Bromo-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(4-Benzenesulfonyl-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(4-Cyclohexyloxy-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
2-Methyl-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-2-ol;
2-Amino-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-1-ol;
3-[4-(3-Methyl-4-phenylsulfanyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
Other preferred compounds of the present invention include those selected from the group consisting of:
3-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-[4-(3-Ethynyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
(3-Methyl-4-phenoxy-phenyl)-[6-(1-methyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine;
(3-Methyl-4-phenoxy-phenyl)-[6-(2-piperidin-3-yl-ethyl)-quinazolin-4-yl]-amine;
3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl-ethyl}-piperidin-3-ol;
3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;
3-Oxo-5-(4-pyrrolidin-1-yl-butyl)-1,2,3,5-tetrahydro-benzo[4,5]imidazo[1,2-a]pyridine-4-carboxylic acid benzylamide;
and the pharmaceutically acceptable salts and solvates of the foregoing compounds.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method of preparing a compound of the formula 1 
and pharmaceutically acceptable salts and solvates thereof, wherein A, X, R1, R4 and R3 are as defined above, which comprises either (a) reacting a compound of the formula 11 or 2 with a compound of the formula 3 
wherein Z is a leaving group and A, X, R1, R4 and R3 are as defined above, or (b) reacting a compound of the formula 7 with a compound of the formula 3 
wherein X, R1, A, R1 and R3 are as defined above and Z1 is an activating group, to provide an intermediate of the formula 5 
wherein Z1, X, R1, A, and R3 are as defined above and Z1 is converted to an R4 group.
xe2x80x9cAbnormal cell growthxe2x80x9d, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serinelthreonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, refers to the act of treating as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties (including fused and bridged bicyclic and spirocyclic moieties), or a combination of the foregoing moieties. For an alkyl group to have cyclic moieties, the group must have at least three carbon atoms.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
The term xe2x80x9calkynylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9c4-10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (xe2x95x90O) moieties is 1,1-dioxo-thiomorpholinyl.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula 1. The compounds of formula 1 that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula 1 are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. Since a single compound of the present invention may include more than one acidic or basic moieties, the compounds of the present invention may include mono, di or tri-salts in a single compound.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
In the compounds of formula 1, where terms such as (CR1R2)q or (CR1R2)t are used, R1 and R2 may vary with each iteration of q or t above 1. For instance, where q or t is 2, the terms (CR1R2)q or (CR1R2)t may equal xe2x80x94CH2CH2xe2x80x94, or xe2x80x94CH(CH3)C(CH2CH3)(CH2CH2CH3)xe2x80x94, or any number of similar moieties falling within the scope of the definitions of R1 and R2. Further, as noted above, any substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, C1-C4 alkoxy and xe2x80x94NR1R2.
In the above compounds of formula 1, where R4 is xe2x80x94(CR1R2)txe2x80x94CR1R11R12, the R12 group is preferably linked through a carbon atom if it is a mono-cyclic ring, and it may be linked through either a carbon atom or a nitrogen if it is a bicyclic ring.
Certain compounds of formula 1 may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula 1, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula 1, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula 1 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. 